P1252: PREDICTING THE RESPONSE OF DLBCL CELLS TO BH3-MIMETICS USING SYSTEMS BIOLOGY
Authors: I. Cloete, V. Smith, R. Jackson, A. Pepper, C. Pepper, M. Dyer, S. Mitchell
Journal: HemaSphere (2022)

Background: Bcl-2 proteins are prominent regulators of mitochondrial-dependent apoptosis in healthy cells and lymphoma. In healthy cells, finely balanced interactions between family members within the Bcl-2 family of proteins ensure normal cell functions. However, in cancerous cells, anti-apoptotic Bcl-2 family members are often overexpressed, tipping the scale towards cell survival. In recent years, therapeutic drugs targeting anti-apoptotic Bcl-2 proteins (BH3-mimetics) have been developed. However, these BH3-mimetics have shown heterogeneous clinical activity in different cancer subtypes, despite Bcl-2 overexpression. Recent experimental studies have suggested that complex interactions between the Bcl-2 family of proteins mediate the response to BH3-mimetics. Therefore, assigning the correct BH3-mimetic to the DLBCL cells in which they will be effective requires predicting the response of the apoptotic molecular signalling network. This response is an emergent property of the abundance of the signalling network’s components along with the binding affinities, regulatory interactions and kinetic rates. Aims: Construct a computational model that enables BH3-mimetics to be tested in virtual DLBCL cell lines and accurately predicts cellular responses, as measured experimentally. Methods: By combining published data including protein abundances, binding affinities, mutational profiles and kinetic rates we construct a computational model of the distinct apoptotic signalling network in multiple DLBCL cell lines. The simulation incorporates experimentally-measured Bcl-2 expression profiles, generating a set of virtual DLBCL cell lines. Bcl-2 (ABT-199), Mcl-1 (S63845) and Bcl-xL (A1331852) inhibitors are simulated to predict cell viability and compared to experimental results. Results: Our virtual DLBCL cell lines recapitulate the Bcl-2 protein expression profiles in DLBCL cell lines. Our computational cell line models recreate how cells expressing distinct abundances of Bcl-2 proteins respond to BH3-mimetics through complex shifts in binding partners between pro-and anti-apoptotic Bcl-2 family proteins. The result of this work is a computational tool that, by simulating the regulatory interactions governing apoptosis, can predict the sensitivity of DLBCL cells to BH3-mimetics (Fig. 1). We validate predicted heterogeneous response of DLBCL cells to BH3-mimetics with experimental data from DLBCL cell lines. Image:Summary/Conclusion: The cellular response to BH3-mimetics is a complex emergent behaviour resulting from a combination of affinity, abundance and genetics, and is therefore challenging to predict. Computational systems biology provides a tool to overcome this challenge. Using a combination of in silico and in vitro experiments, we show that a computational model can predict the sensitivity of a cell to targeted therapies. Future work will test the ability of the model to predict patient responses to targeted therapies in order to enable a personalised medicine approach.